The principal organs of the human female reproductive tract include the ovaries, fallopian tubes, uterus, and the vagina. The vagina comprises a musculomembranous tube which forms the passageway between the uterus and the entrance to the vagina between the external vulvae. The vulvae include the labia majora, consisting of two folds of cellular adipose tissue lying on either side of the vaginal opening which form the lateral borders of the vulva. The labia minora lies within the labia majora and encloses the vestibule of the vagina. The vestibule is an almond-shaped space between the lines of attachment of the labia minora. The covering membranes of the vestibule are constructed of delicate, non-keratinized, stratified squamous epithelium.
Vulvar vestibulitis syndrome is an inflammatory process of the vestibule of the vagina which involves the mucous membrane and its underlying appendages, the lesser vestibular ducts and glands. It is characterized by a variety of symptoms, including severe pain on vestibular touch or vaginal entry, tenderness to pressure localized within the vulvar vestibule, and erythema confined to the vestibule.
Vulvar vestibulitis is extremely common. In fact, it has been estimated that approximately 15% of women visiting their gynecologist have vulvodynia or vulvar vestibulitis. Goetsh, M. F., Vulvar vestibulitis: Prevalence and historic features in a general gynecologic practice population: Amer. J. Obstet. & Gynecol., 1991; 164: 1609-1616.
Vulvar pain and its associated problems of dysparunia (pain during sexual intercourse) and vaginismus, or spasm of the leavator muscles, was first described by Skene over one hundred years ago when he wrote about the finding of "excessive sensitivity or hyperesthesia" of the vulva. Skene, A. J. C.; Treatise on Disease of Women, 1889; Apleton and Company, New York. Subsequently, in 1928, Kelly described finding "exquisitely sensitive deep red spots in the mucous of the hymeneal ring" and hypothesized that it could be the source of dysparunia. Kelly, H. A., Gynecology 1928; Apleton and Company, New York. Since that time, vulvar pain and the inability to have intercourse has been called vulvodynia or vaginismus, and was thought to be predominantly a psychological disorder.
Recently, Woodruff and Parmley described a lesion associated with vulvar pain which was erythematous and confined to the vestibule of the vagina and recommended a surgical approach for therapy. Woodruff, J. D. and Parmley, T. H.; Infection of the minor vestibular gland; Obstet. & Gynecol., 1983; 62: 609-612. Later, Freidrich described the lesion in greater detail, named it vulvar vestibulitis syndrome, and concurred that the surgical approach was necessary in most cases. Freidrich, E. G.; Vulvar vestibulitis syndrome: J. Reprod. Med., 1987; 32: 110-114.
Women suffering from vulvar vestibulitis have varying degrees of pain from mild discomfort to severe wherein the woman is unable to walk and/or experiences pain with intercourse. Intercourse in most patients is impossible due to the severity of the pain with insertion and thrusting. Following intercourse, there is usually swelling and pain for several hours to several days. Vulvar vestibulitis can last for years and places a great burden on any relationship the individual may have. Patients with vulvar vestibulitis typically show erythema, occasionally erosion, hypertrophy of the vestibular ducts, and extreme tenderness when the area is touched with a cotton tipped applicator.
The cause of vulvar vestibulitis is uncertain, with yeasts, human papilloma viruses, contact irritants, and other factors being suggested as possible causes. The symptoms vary in their severity, from periods of relative comfort to periods of excruciating pain. These episodes are unpredictable as to their frequency, duration, or severity of pain. Women with vulvar vestibulitis must not only learn how to cope with the chronic nature of this problem, but frequently with a partner who may or may not be understanding when they are unable or unwilling to have sexual intercourse because of pain. Many of these individuals suffer depression and a number of couples, unwilling to deal with the long term nature of this problem, separate, leaving the person with the disease devastated, feeling inadequate, and willing to attempt any therapy that may have some promise of alleviating the pain.
Currently, surgery, laser therapy, and interferon therapy are the treatments most commonly recommended to patients with vulvar vestibulitis. Surgical removal of the vestibule and its underlying structures is appealing to both the physician and the patient, since it offers a quick and decisive approach. However, surgery is a mutilating procedure leaving the area disfigured and scarred and, in most patients, the ameliorative affect is short, with the return of symptoms in many cases in less than twelve months.
Laser therapy or laser surgery is also disadvantageous since it disfigures the skin, causes hyperestesia in many patients, and its effects are commonly of short duration. Topical steroid therapy has had some benefit in these individuals by decreasing the amount of inflammation in the tissues of the vestibule. However, cortical steroid therapy causes atrophy of the skin, especially in the thinner more delicate mucosal areas and, therefore, long-term use is not feasible. Oral analgesic or anti-inflammatory medications, either steroid or non-steroid, have not shown any beneficial effects in these patients. Anti-depressive medication, counseling and behavior modification techniques are helpful, but do not treat the underlying pain. Recently, relaxation exercises have been proposed to relieve the underlying muscle spasm, but again they do not relieve the pain of the vestibule.
There is therefore a need for a treatment for vulvar vestibulitis which is not disfiguring or harmful to the vestibular tissue, yet which is also effective in treating the pain.
It is believed that in a majority of patients, the disease would improve significantly with time by using conservative topical treatment and allowing the normal immune response to control the underlying process. In order to do this effectively, the drug product must control pain without damaging the integument of the vestibule. In addition, the product should be non-irritating, non-staining, hypoallergenic, and user friendly. None of the products currently available, however, control the pain associated with vulvar vestibulitis. There are also problems with the current delivery systems, especially when applied to the vulva.
The three classes of vehicles/delivery systems that are commonly and widely used in topical preparations for vaginal use are ointments, creams, and water soluble polymers or polymer gels. Ointments are derived from either petrolatum hydrocarbon products or animal fats. The animal fat products are exemplified by lanolin or wool fat. Ointments suffer severe disadvantages when utilized for administration to mucosal surfaces, either in the rectum or vagina. First, ointments are occlusive, placing an oleaginous covering over skin or mucosa which prevents or restricts the ability of the underlying tissue to transpire. This results in maceration of the tissue, which is further exacerbated if the tissue is already irritated. In addition, being oily products which become more fluid at body temperature, ointments tend to soften and flow and stain clothing.
Creams or lotions are either oil-in-water or a water-in-oil emulsion systems. The water-in-oil emulsions have some of the same disadvantages as do ointments since they have an oil external phase. Both classes of emulsions, however, of necessity, contain surface-active or emulsifying agents. These materials are irritating to the eye and to mucus membranes. The irritation is compounded if the membranes are already irritated or compromised.
The polymeric gel or water soluble polymeric carrier system is the newest of the three classes of delivery systems, even though it has been available for around fifty years. This type of system is exemplified by the polyethylene glycols. Combinations of the polyethylene glycols, differing in molecular weight, produce semisolid topical carriers ranging in viscosity and consistency. Other soluble polymers, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, poly(acrylic acids), etc., are used to produce gels, which serve as topical vehicles. All of the materials in this class are highly water soluble. However, these products do not adhere well to wet mucosal surfaces and are quickly released from such surfaces by the moisture that is present, or due to vaginal expansion in response to sexual stimulation. Further, these materials often are also irritating to mucosal surfaces based on their high affinity for water and their tendency to dehydrate and overly dry the mucosal surfaces to which they are applied. The patient often experiences a burning sensation following the application of these delivery systems to the mucosal surface.
The present inventors have now discovered that the use of a non-steroidal anti-inflammatory drug (NSAID) incorporated in a novel aqueous based carrier system is effective for treating the pain associated with vulvar vestibulitis without harming the vestibular tissue. The composition is also effective for treating other inflammatory disorders affecting mucosal and non-keratinized epithelial tissues.
Accordingly, it is a primary objective of the present invention to provide a composition and method for treating inflamed human mucosal and epithelial tissues using a non-steroidal anti-inflammatory drug.
It is a further objective of the present invention to provide a composition and method for treating inflamed human mucosal and epithelial tissues which is effective in decreasing the amount of pain associated with the inflammation.
It is a further objective of the present invention to provide a composition and method for treating inflamed human mucosal and epithelial tissues which is not disfiguring or harmful to the tissues.
It is yet a further objective of the present invention to provide a composition and method for treating inflamed human mucosal and epithelial tissues which is oil-free and nonirritating.
It is still a further objective of the present invention to provide a composition and method for treating inflamed human mucosal and epithelial tissues which is easy to use and economical to manufacture.
The method and means of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereafter.